Advanced
hormone-sensitive
prostate cancer responds to
androgen-deprivation
therapy (ADT); however, therapeutic options for recurrent
castration-resistant disease are limited. Because
growth hormone-releasing hormone (GHRH) and
GHRH receptor (GHRH-R) are regulated in an autocrine fashion in
prostate cancer, inhibition of GHRH-R represents a compelling approach to treatment. We investigated the effects of the latest series of improved, highly potent GHRH antagonists--MIA-602, MIA-606, and MIA-690--on the growth of
androgen-dependent as well as
castration-resistant
prostate cancer (CRPC) cells in vitro and in vivo. GHRH-R and its splice variant, SV1, were present in 22Rv1, LNCaP, and VCaP human
prostate cancer cell lines.
Androgen-dependent LNCaP and VCaP cells expressed higher levels of GHRH-R
protein compared with
castration-resistant 22Rv1 cells; however, 22Rv1 expressed higher levels of SV1. In vitro,
MIA-602 decreased cell proliferation of 22Rv1, LNCaP, and VCaP
prostate cancer cell lines by 70%, 61%, and 20%, respectively (all P < 0.05), indicating direct effects of
MIA-602. In vivo,
MIA-602 was more effective than MIA-606 and
MIA-690 and decreased 22Rv1 xenograft
tumor volumes in mice by 63% after 3 wk (P < 0.05). No noticeable untoward effects or changes in
body weight occurred. In vitro, the VCaP cell line was minimally inhibited by
MIA-602, but in vivo, this line showed a substantial reduction in growth of xenografts in response to
MIA-602, indicating both direct and systemic inhibitory effects.
MIA-602 also further inhibited VCaP xenografts when combined with ADT. This study demonstrates the preclinical efficacy of the GHRH antagonist
MIA-602 for treatment of both
androgen-dependent and CRPC.